Introduction
Several respiratory disorders remain incurable despite the advancements in treatment strategies. Regenerative medicine is a new therapeutic approach for treating various diseases, specifically those associated with the immune system. Different therapeutic approaches have emerged in treating respiratory conditions as a measure to restore functional lung tissue rather than treating the symptoms. These therapeutic methods use stem cells and their derivatives to replace dysfunctional lung tissue using biomedical engineering. Advancements in lung development and repair have improved therapeutic options for a range of lung diseases.
What Is the Significance of Regenerative Medicine in Lung Repair?
Acute and chronic lung diseases result in a loss of functional lung tissue. In patients with end-stage lung disease who are refractory to various treatment procedures, lung transplantation is the only treatment option available. Though lung transplantation is a life-saving procedure, it has limitations, such as a shortage of the donor's lungs and rejection of the transplanted lung. Regenerative medicine helps repair the loss of lung tissues that require transplantation and the progressive loss of lung function. Regenerative approaches to repair lung tissue include cell therapy, pharmacological interventions, and extracellular vesicles, and those aimed at replacement include cell therapy and tissue engineering.
In addition, the lung has the ability to regenerate in response to tissue injury. However, lung tissue regeneration can result in pathological tissue remodeling, which leads to impairment of lung function. These pathological changes in the lung can be reversed via regenerative medicine in the form of extracellular vesicle therapy, cellular therapy, or tissue engineering.
What Is the Role of Cellular Therapy in Lung Repair?
Regenerative cell therapy is the widely used approach for stimulating the regeneration of damaged lung tissue. Stem cells play a vital role in regenerative stem cell therapy. Stem cells are undifferentiated cells that are capable of self-renewal and can transform into other cell types. Stem cells in the body have the ability to migrate to the affected tissue and replace the damaged tissue.
Cellular therapy involves two approaches, namely, the induction of endogenous stem cells and the mobilization of resident progenitor cells and the exogenous development of stem cells and their application in patients with lung diseases. The induction of endogenous stem cells (stem cells within the host) is related to lung tissue regeneration and repair through the activation of the resident cells in the host, while the exogenous development of stem cells is associated with immunomodulatory effects and paracrine action.
Multiple stem cells and progenitor cells in the airways can differentiate into various airway cell types. Basal epithelial cells serve as progenitors for various airway cells that are capable of regeneration and repair. Submucosal glandular progenitor cells type 2 alveolar cells, and neuroendocrine cells of the lung are progenitor cells that differentiate into cells that are capable of regeneration. Exogenous stem cells play a role in immunomodulation. Various stem cell sources, such as adipose-derived stem cells, umbilical cord-derived mesenchymal stem cells, and embryonic stem cells, have been investigated regarding their therapeutic use in lung regeneration and repair.
What Is the Impact of Lung Tissue Remodeling on Lung Repair?
The role of lung epithelial cells in repair and regeneration depends on the cues from the surrounding niche. The profibrotic and proinflammatory cues (signals from the microenvironment) in lung diseases contribute to lung tissue remodeling and repair of the dysregulated lung tissues. In addition, changes in the composition of the extracellular matrix and variations in the mechanical cues caused by increased stiffness in fibrotic tissues or an increase in stiffness in regions of destruction or mechanical ventilation may alter the process of differentiation and repair. Though acute proinflammatory cues may promote alveolar (air sacs in the lungs) differentiation, prolonged inflammation may impair the process of alveolar maturation and the regeneration of alveoli.
What Are the Therapeutic Approaches for Lung Repair and Regeneration?
A better knowledge of the mechanisms of respiratory development and repair pathways, the stem cells, growth factors, and other signaling molecules provides the basis for interventional strategies. Various clinical studies have evaluated the efficiency of the following approaches in lung repair and regeneration.
-
Tissue Engineering:
Sometimes cellular therapy and stimulation of tissue regeneration are insufficient to manage pathological changes in chronic lung diseases, and tissue replacement may be required to restore the function of the lung tissues. Also, suitable lung donors are not available most of the time, or lung transplantation is contraindicated. Hence, laboratory-grown lung tissue may help overcome these limitations. However, in-vitro (in the laboratory) generation of lung tissue that mimics lung function is a complex and challenging procedure and requires a high degree of specialization.
-
Cell-Free Therapeutic Approaches:
Extracellular vesicles carry various substances, including microRNA (Ribonucleic acid), proteins, mitochondria (the powerhouse of the cell), and messenger RNA. Extracellular vesicular therapy has several advantages over cellular therapy. Extracellular vesicles can penetrate deep into the airways and can be delivered through inhalation techniques. Extracellular vesicle therapy has shown various benefits in the treatment of pulmonary fibrosis and lung injury. It enhances alveolarization and morphogenesis and restores lung tissue homeostasis. In addition, it also limits respiratory infections caused by viruses. Various clinical studies have demonstrated that systemic administration of extracellular vesicles alleviates allergic hyperactivity and tissue remodeling. Though extracellular vesicle therapy offers multiple benefits in lung tissue regeneration and repair, it lacks standardization for the isolation and purification of extracellular vesicles.
-
Regenerative Pharmacology:
The role of mesenchymal cell-derived fibroblast growth factor in lung regeneration and repair was evaluated. Various clinical studies also assessed the role of human lipopolysaccharides, retinoids, retinoic acid receptors, and drugs that target senescence to stimulate lung repair and regeneration. These studies did not show therapeutic advantages and had limitations. Hence, these drugs were not approved for use in lung regeneration and repair. However, pharmacotherapy using mesenchymal stem cells showed a significant reduction in lung inflammation at the time of administration. Also, the conditioning of mesenchymal stem cells or gene editing may enhance the regenerative properties of mesenchymal stem cells.
Conclusion
Though multiple pharmacological and cellular therapies have been evaluated in animal models, the regenerative approaches in clinical trials for lung diseases have been limited. Further evidence from clinical trials is required before accepting regenerative therapy as a therapeutic approach in respiratory medicine. It is also essential to focus on the functional heterogeneity of each cell in the respiratory system for understanding and developing protocols for targeted cell regeneration and repair.
